Hypothesis Comparison

graph TD
    A["Cellular Senescence
Astrocytes and Microglia"] -->|"Triggers"| B["SASP Activation
Senescence-Associated
Secretory Phenotype"]
    B -->|"Secretes"| C["Pro-inflammatory
Cytokines
IL-1beta, TNF-alpha, IL-6"]
    B -->|"Releases"| D["Complement Initiators
C1q, C3, C4"]
    B -->|"Produces"| E["Chemokines and
Matrix Proteases
CCL2, MMP3"]
    
    D -->|"Activates"| F["Classical Complement
Pathway Initiation
C1q-C1r-C1s Complex"]
    F -->|"Cleaves"| G["C4 and C2
Formation of
C3 Convertase C4b2a"]
    G -->|"Amplifies"| H["C3 Cleavage
C3a and C3b
Generation"]
    
    H -->|"Forms"| I["C5 Convertase
C4b2a3b Complex
Alternative Pathway Feed-in"]
    I -->|"Generates"| J["C5a Anaphylatoxin
Microglial
Chemotaxis Signal"]
    I -->|"Initiates"| K["Terminal Pathway
C5b-9 Membrane
Attack Complex"]
    
    H -->|"Opsonizes"| L["Synaptic Tagging
C3b Deposition on
Neuronal Synapses"]
    L -->|"Recognized by"| M["Microglial CR3
Complement Receptor 3
CD11b-CD18"]
    M -->|"Triggers"| N["Complement-Mediated
Synaptic Pruning
Phagocytosis"]
    
    J -->|"Activates"| O["Microglial Migration
and Activation
M1 Polarization"]
    O -->|"Enhances"| N
    C -->|"Amplifies"| O
    
    N -->|"Results in"| P["Progressive Synapse Loss
Before Plaque Formation
Early AD Pathology"]
    P -->|"Leads to"| Q["Cognitive Decline
Memory Impairment
Neurodegeneration"]
    
    R["Therapeutic C1q-C3
Inhibition in SASP
Microenvironments"] -->|"Blocks"| D
    R -->|"Prevents"| F
    
    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0
    
    class A,B,C,D,E normal
    class F,G,H,I,J,K,L,M molecular
    class N,O,P pathology
    class Q outcome
    class R therapeutic

graph TD
    A["Senescent Astrocytes
and Neurons"]
    B["SASP Factors
(IL-1beta, TNF-alpha, Lactate)"]
    C["Microglial Receptors
(IL-1R, TNFR1, MCT)"]
    D["NF-kappaB and
mTORC1 Activation"]
    E["HK2 Gene
Transcription"]
    F["PFKFB3 Gene
Transcription"]
    G["HK2 Protein
Mitochondrial Association"]
    H["PFKFB3 Protein
Fructose-2,6-BP Production"]
    I["Enhanced Glycolytic
Flux"]
    J["ATP Production
and Lactate Accumulation"]
    K["Acidic Microenvironment
pH Decrease"]
    L["Complement Cascade
(C1q, C3) Activation"]
    M["Phagocytic Machinery
Protein Synthesis"]
    N["Drp1-Mediated
Mitochondrial Fragmentation"]
    O["Reduced Oxidative
Phosphorylation"]
    P["Synaptic Tagging
Recognition"]
    Q["Synaptic Phagocytosis
and Neurodegeneration"]

    A -->|"releases"| B
    B -->|"binds to"| C
    C -->|"activates"| D
    D -->|"upregulates"| E
    D -->|"upregulates"| F
    E -->|"produces"| G
    F -->|"produces"| H
    G -->|"enhances glucose
phosphorylation"| I
    H -->|"activates PFK-1"| I
    I -->|"generates"| J
    J -->|"creates"| K
    K -->|"activates"| L
    I -->|"supports"| M
    I -->|"promotes"| N
    N -->|"causes"| O
    L -->|"enables"| P
    M -->|"facilitates"| Q
    P -->|"leads to"| Q
    J -->|"reinforces glycolytic
phenotype"| I

    classDef normal fill:#4fc3f7
    classDef therapeutic fill:#81c784
    classDef pathology fill:#ef5350
    classDef outcome fill:#ffd54f
    classDef molecular fill:#ce93d8

    class A,C,G,H normal
    class E,F,D molecular
    class B,I,J,K,L,N,O,P pathology
    class M,Q outcome